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Article

“Super-Responders” to Liraglutide Monotherapy and the Growing Evidence of Efficacy of GLP-1 Analogues in Obesity Management: A Longitudinal Prospective Cohort Study

by
Ellina Lytvyak
1,*,
Eduardo Grunvald
2,
Devika Shreekumar
3,
Peter Rye
4,
Olexandr Troshyn
5,
Sarah Cawsey
6,
Aldo J. Montano-Loza
3,
Arya M. Sharma
6 and
Renuca Modi
7,8
1
Division of Preventive Medicine, Department of Medicine, University of Alberta, 5-30 University Terrace, 8303 112 Street, Edmonton, AB T6G 2T4, Canada
2
Center for Advanced Weight Management, UCSD Bariatric and Metabolic Institute, Division of General Internal Medicine, University of California San Diego, 4303 La Jolla Village Drive, Suite 2110, San Diego, CA 92122, USA
3
Division of Gastroenterology and Liver Unit, University of Alberta, 8540 112 Street NW, Zeidler Ledcor Centre, Room 1-20B, Edmonton, AB T6G 2X8, Canada
4
Calgary Adult Bariatric Specialty Clinic, South Health Campus, General Internal Medicine, 4448 Front Street SE, Calgary, AB T3M 1M4, Canada
5
Department of Medicine, University of Alberta, 13-103 Clinical Sciences Building, 11304 83 Ave NW, Edmonton, AB T6G 2B7, Canada
6
Division of Endocrinology and Metabolism, Department of Medicine, University of Alberta, 13-103 Clinical Sciences Building, 11304 83 Ave NW, Edmonton, AB T6G 2B7, Canada
7
Edmonton Adult Bariatric Specialty Clinic, Royal Alexandra Hospital, Edmonton, Royal Alexandra Hospital CSC 472, 10240 Kingsway Avenue, Edmonton, AB T5H 3V9, Canada
8
Department of Family Medicine, University of Alberta, 5-16 University Terrace, 8303 112 Street, Edmonton, AB T6G 2T4, Canada
*
Author to whom correspondence should be addressed.
Obesities 2025, 5(3), 63; https://doi.org/10.3390/obesities5030063
Submission received: 16 June 2025 / Revised: 12 August 2025 / Accepted: 19 August 2025 / Published: 20 August 2025
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Abstract

Aims: Individual weight loss results achieved with Glucagon-like Peptide-1 receptor agonists (GLP-1RA) vary significantly. Our aim was to describe the characteristics of patients with obesity who achieved ≥ 20% total weight loss (TWL) on liraglutide and appraise those findings through the prism of an evolving spectrum of GLP-1RA. Methods: This longitudinal prospective cohort study included 21 patients (90.5% females, age 50 (IQR 17) years, class II/III obesity (Body Mass Index ≥ 35 kg/m2) followed at the Edmonton Adult Bariatric Clinic for 65.1 (IQR 15.5) weeks. All patients received treatment with liraglutide 3.0 mg subcutaneously daily along with involvement in an integrated lifestyle modification program. Results: Liraglutide was well-tolerated, with its benefits experienced by >90% of patients. The vast majority were consistently tracking calories (95.2%, n = 20) and protein intake (90.5%, n = 19), achieving a calorie deficit of 651 (IQR 323) kcal/day, and had their mental health conditions and psychological issues successfully managed. At 16, 26, and 52 weeks, TWL was 14.3% (IQR 3.7), 18.7% (IQR 8.8), and 25.9% (IQR 9.6), respectively (p < 0.001). Over 20% TWL was achieved by 72.2% of patients by week 52. Conclusions: A select number of patients with obesity will attain weight loss that rivals bariatric surgery using liraglutide monotherapy. Despite liraglutide being less effective compared to newer agents on the market, some individuals will respond strongly and should be considered when other therapies are inaccessible. Given the societal burden and numerous challenges faced by people with obesity, GLP-1RA should be pursued in clinical practice to assist in achieving weight loss goals while being convenient and safe.

1. Introduction

Over 2 billion adults worldwide live with overweight and obesity, and this burden is predicted to increase without immediate intervention [1,2,3]. Multiple comorbidities, such as type 2 diabetes (T2D), cardiovascular disease, gallbladder disorders, lower back pain, osteoarthritis, different types of cancers, and a plethora of others, have been strongly linked to obesity [4,5,6]. Weight loss leads to a substantial improvement in overall health and quality of life, and a reduction in morbidity and mortality [7].
Bariatric surgery has been a viable option for people living with obesity and adiposity-associated comorbidities. Total weight loss (TWL) at 1-year post-surgery ranges between 23.6% and 34.8% for sleeve gastrectomy and between 27.0% and 37.1% for Roux-en-Y gastric bypass [8]. However, recent pharmaceutical agents have revolutionized obesity management. The unique mechanism of action of Glucagon-like Peptide-1 receptor agonists (GLP-1RA) involves augmentation of insulin synthesis and secretion, inhibition of glucagon secretion, delayed gastric emptying, enhancement of satiety and satiation, and modified food perception [9]. GLP-1RA such as liraglutide and semaglutide were initially approved for treating T2D and continue to reveal a significant reduction in the risk of adverse cardiovascular outcomes and nephropathy [10]. More recently, large randomized controlled trials (RCTs), including SCALE, LEADER, SUSTAIN, and STEP, have provided robust evidence demonstrating the weight loss potential of GLP-1RA [9,11,12,13,14,15,16].
In large RCTs, liraglutide demonstrated 9.2% mean weight loss among patients with obesity, while semaglutide at a daily dose of 0.4 mg sc revealed a capacity to reduce weight by 18.0% below baseline after a year of treatment [15]. Similarly, tirzepatide, offering a combination of GLP-1RA and a glucose-dependent insulinotropic polypeptide (GIP) agonist, demonstrated comparable results with 20.9% weight loss in patients with excess weight without T2D and 14.7% in patients with T2D after 72 weeks of treatment [14,17].
In clinical practice, individual weight loss results achieved on GLP-1RA vary significantly, and some patients achieve weight loss results that rival bariatric surgery. There are very few studies published regarding such “super-responders” [18]. Currently, liraglutide is the only GLP-1RA that can be prescribed in its generic form, and hence may be more widely available for patients who do not have insurance coverage for other incretin-based anti-obesity medications (AOMs). Our aim was to describe and better understand the shared characteristics and behaviors of patients with obesity who achieved ≥ 20% TWL on liraglutide and appraise those findings through the prism of an evolving spectrum of GLP-1RA.

2. Subjects, Materials and Methods

All subjects were identified among patients followed at the Edmonton Adult Bariatric Clinic, a Canadian tertiary care center, between October 2015 and April 2018; their charts were reviewed retro- and prospectively. The inclusion criteria for study participants were age ≥ 18 years, class II or III obesity (body mass index [BMI] ≥ 35.0 kg/m2), monotherapy with liraglutide, and the achievement of ≥20.0% TWL while treated. Exclusion criteria included the use of other AOMs, severe morbidities (infection with human immunodeficiency virus, hepatitis B and C, liver cirrhosis, heart failure), and significant intellectual disability. Out of 1910 patients followed, including 724 (37.9%) treated with liraglutide, 21 patients (2.9% of those treated with liraglutide) met the inclusion and exclusion criteria. Obesity stage was established as per the Edmonton Obesity Staging System (EOSS), which classifies patients into stages of obesity by taking into consideration metabolic consequences, biomechanical complications, and severity of functional and psychosocial impact, providing a more comprehensive understanding of the wide-ranging health effects associated with excess weight [19]. Diagnosis of adiposity-related complications was established according to the most up-to-date guidelines. The last follow-up was defined as the date of the most recent appointment before bariatric surgery or within the study timeframe. One patient was lost to follow-up before the 26-week timepoint as they were not a surgical candidate due to multiple comorbidities. Two more patients were lost to follow-up before 52 weeks, as they lost contact with the healthcare system. All patients were offered an integrated lifestyle modification program, monitored by an obesity medicine specialist certified by the American Board of Obesity Medicine, registered dietitian, psychologist and/or psychiatrist (if indicated), and registered nurse with an overarching goal of reducing calorie intake, self-monitoring food intake, psychological support, and increase in physical activity as tolerated.
Descriptive statistics were calculated. Because weight and BMI values were not normally distributed, non-parametric statistical methods were applied for baseline characteristics analysis and over-time comparison for all continuous variables. Continuous data were presented as median (IQR) and categorical data as proportions (counts). Percent of Total Weight Loss (%TWL) was defined as the difference between the weight at a given timepoint (16, 26, 52 weeks, and last follow-up) and the weight at the baseline divided by the weight at the baseline. It was chosen as the most reliable measure reflecting weight loss, as a significant body of evidence demonstrates that it is less influenced by baseline BMI.
Friedman’s two-way analysis of variance by ranks test, followed by Wilcoxon signed-rank test for pairwise comparisons, was used to assess the trends in parameters over time. Statistical analysis was performed using SPSS 23.0 and GraphPad 6.0, with a p-value ≤ 0.05 indicating statistical significance.

3. Results

3.1. Characteristics of Patients and Their Weight Status at Baseline

The baseline demographic and clinical characteristics of patients included in the study are presented in Table 1. Twenty-one patients included were mainly female (90.5%, n = 19) and Caucasians (90.5%, n = 19), with a median age of 50 years (IQR 17).
All patients had class II or III obesity, and 42.9% (n = 9) had a BMI ≥ 50 kg/m2. All patients were on the highest dose of liraglutide at 3.0 mg subcutaneously (sc) daily. Twenty patients (95.2%) had obesity-related comorbidities, with the most common being obstructive sleep apnea (57.1%, n = 12) and hypertension (42.9%, n = 9). Nineteen patients (90.5%) had stage 2 obesity according to the EOSS, and the remaining two patients had stage 1 and 3 [19]. Three patients (14.3%) had prior bariatric surgery, 14 (66.7%) were interested in future bariatric surgery, and 11 of those (78.6%) proceeded with it afterwards.
Most patients had a history of problematic eating behaviors, including emotional eating (85.7%, n = 18), binge eating (38.1%, n = 8) and/or binge eating disorder (9.5%, n = 2). Several patients had a history of mental health issues such as major depressive disorder (MDD) (42.9%, n = 9), generalized anxiety disorder (GAD) (23.8%, n = 5), attention deficit hyperactivity disorder (ADHD) (9.5%, n = 2) and personality disorder (4.8%, n = 1). A history of abuse, including sexual, emotional, and physical (28.6%, n = 6), and addiction, including alcohol and recreational drugs (9.5%, n = 2), was present as well.

3.2. Adherence with Treatment and Lifestyle Modifications Recommendations

Shared characteristics regarding adherence with the recommended lifestyle modifications, as well as treatment, are outlined in Table 2. All patients with GAD, ADHD, and 77.8% (n = 6) of patients with MDD were receiving appropriate treatment. Binge eating behavior was successfully managed by the psychologist in 75% of patients (n = 6) and emotional eating in 66.7% (n = 12).
Over 90% of patients reported consistently tracking their calorie and protein intake, and over 80% were able to establish and maintain a regulated routine meal pattern, meet a protein target and be engaged in regular physical activity. Patients were engaged in various forms of physical activity, including walking with a target of 10,000 steps per day, biking, yoga, and recreational activities such as gardening.

3.3. Benefits and Side Effects of Liraglutide

Benefits and adverse events experienced by the patients on liraglutide are demonstrated in Table 2. Hunger reduction, reduced portion sizes and healthier food preferences were the most common benefits experienced by over 90% of patients. The majority of patients also reported increased satiety (81.0%, n = 17) along with decreased frequency and intensity of cravings (66.7%, n = 14). Patients were able to successfully achieve a 651 kcal (IQR 323) daily calorie deficit.
The most common side effect was constipation, experienced by almost half of the patients (47.6%, n = 10), followed by nausea (42.9%, n = 9) and dysgeusia (33.3%, n = 7). Headache was the most commonly occurring systemic side effect (23.8%, n = 5). While adverse effects were relatively common, in all cases they were mild, well-tolerated, and transient, occurring during the time of dose escalation and decreasing or fully disappearing thereafter. No patient among our cohort discontinued therapy due to treatment-related symptoms.

3.4. Changes in Weight Status During Treatment

Changes in weight status during liraglutide treatment are presented in Table 2. At liraglutide initiation, median weight was 123.6 kg (IQR 34.9), ranging from 93.5 to 215.0 kg, with median BMI being 45.7 kg/m2 (IQR 7.4). Almost half of the patients (47.6%, n = 10) were at their lifetime peak weight at liraglutide initiation. At 16 weeks post-treatment initiation, weight declined to 109.1 kg (IQR 23.3), reflecting a 14.3% (IQR 3.7) TWL (Figure 1 and Figure 2). Sixteen patients (76.2%) lost ≥ 10% of weight during the first 4 months on liraglutide (Figure 3). At 26 weeks, weight decreased to 99.3 kg (IQR 19.6) and then, by 52 weeks, to 91.3 kg (IQR 18.4) representing 18.7% (IQR 8.8) and 25.9% (IQR 9.6) TWL, respectively. Two patients (9.5%) achieved ≥ 20% weight loss by 16 weeks, eight (40.0%) by 26 weeks, and thirteen (72.2%) by 52 weeks. By the last follow-up, all the patients exceeded 20% TWL. The largest %TWL attained over the course of treatment was 27.5% (IQR 7.4) with a range between 22.4% and 41.9%. To note, the time interval to nadir weight varied substantially, from 44.0 to 89.7 weeks, with a median of 65.1 (IQR 15.5) weeks.
Weight was significantly different at all the consecutive timepoints during the treatment course (p < 0.001). In a pairwise comparison, there was a statistically significant decrease in weight between all sequential timepoints and the baseline (p < 0.001), between 16, 26, and 52 weeks (p < 0.001), and also between baseline weight and weight at the last follow-up (p < 0.001).

4. Discussion

The presented longitudinal prospective cohort study demonstrates that with liraglutide treatment, coupled with lifestyle and behavior modification, a number of patients with obesity can achieve ≥ 20% TWL. According to our results, the median %TWL at the 52-week timepoint was 25.9% (IQR 9.6), ranging from 13.3% to 33.2%. It markedly exceeds the results observed on liraglutide treatment in RCTs, where %TWL at 1 year varied between 4.0% and 9.2%, which would allow us to consider our patients to be “super-responders” [11,12].
It is important to note that in trials that compared the efficacy of GLP-1 and GLP-1/GIP agonists between different baseline BMI subgroups, there were no baseline BMI-dependent effects on relative weight loss [16,20,21,22]. In the study by le Roux et al. involving over 3500 individuals, the %TWL at 56 weeks among those with class II obesity was 7.9% compared to 8.2% among those with baseline BMI between 27.0 and 34.9 kg/m2, with no significant difference between the two groups [22]. In SUSTAIN 1-5 trials, exploring the efficacy of semaglutide, individuals with class II obesity at baseline demonstrated the greatest relative weight loss in comparison to other baseline BMI categories that varied between 5.9% and 7.9%; however, the magnitude of weight loss did not differ significantly across the groups [16]. The proportion of people with class II obesity achieving 10% TWL at 56 weeks in SUSTAIN 2 and 3 was 23% and 21%, respectively, comparable to other baseline BMI groups and substantially lower than observed in our longitudinal prospective cohort study (100%) [16]. In SURPASS 1-5 studies, relative weight loss was also comparable across different baseline BMI subgroups [20,21].
Evidence suggests that early response to weight-loss intervention is predictive of successful weight loss at 1 year. Among patients in our study, at 16 weeks, the observed TWL was 14.3% (IQR 3.7) and ranged from 4.3% to 28.4%. These findings are consistent with the literature where ≥4% TWL at week 16 on liraglutide was predictive of the clinically meaningful weight loss of ≥15% TWL at 1-year post-treatment initiation, with 21.3% of those “early-responders” achieving this target [23]. In our study, 94.4% (n = 17) of patients attained this clinically meaningful weight loss target of ≥15% TWL by 52 weeks.
It is recognized that there is tremendous heterogeneity with respect to weight loss outcomes with any intervention for obesity, including pharmacotherapy. As such, all cohorts in a given treatment group will include individuals far above the mean weight loss outcomes, defined as strong responders. In clinical settings, this is important to recognize as individual therapeutic decisions should be informed by more than just the mean weight loss reported in clinical trials. In fact, categorical data presented in studies may perhaps be more relevant.
The achievement of ≥20% TWL through non-surgical intervention has been documented elsewhere. In 43 patients who qualified for bariatric surgery, Cadegliani et al. reported achieving a 25.7% TWL with 74.4% of patients losing ≥ 20%. This was achieved through an aggressive regimen that combined structured lifestyle change, psychotherapy, and polypharmacotherapy [24]. Notably, 90.7% of patients were on a regimen that included liraglutide. The authors concluded that 93% of patients were able to avoid bariatric surgery.
The specific forces that determine the magnitude of response are not well known. They are likely related to behavioral, lifestyle, clinical, metabolic, and genetic factors that are not easy to separate or isolate as predictive. All patients in our series were adherent to pharmacological anti-obesity treatment with liraglutide, and the vast majority were compliant with diet and physical activity recommendations. Nearly all of our patients experienced the neurobiological benefits of liraglutide, with over 90% reporting hunger reduction, consuming smaller portions and making healthier food choices along with increased satiety and lower frequency and intensity of cravings. With liraglutide specifically, these behavioral factors may be quite important. Previous research has demonstrated the synergistic effect between AOMs and intense lifestyle interventions (ILI) [13]. Similar outcomes were seen with liraglutide in the SCALE IBT Trial [12].
In contrast, compared to less intense lifestyle counseling, ILI did not seem to significantly enhance weight loss outcomes over 68 weeks with semaglutide or tirzepatide over 72 weeks, highlighting that applications of ILI may be more germane to liraglutide efficacy [13,25]. Our findings are consistent with the previously published literature showing that patients who adhere to treatment recommendations utilizing a multidisciplinary approach demonstrate success in achieving and maintaining weight loss [26,27].
Weight-loss outcomes attained by the patients in our study are encouraging. At the time of our study, all patients in our clinic were offered ILI, similar to the approach applied in clinical trials. However, such “super-responders” included in our longitudinal prospective cohort study represent an estimated less than 3% of our clinic’s patients on liraglutide, despite the opportunity to be involved in an IBT and continuous monitoring by an Obesity Medicine specialist, registered dietitian, psychologist, and registered nurse. Interestingly, the weight loss outcomes in our series are much higher than the mean 7.5% weight loss seen in the SCALE IBT Trial [12]. Therefore, we speculate that the findings in the present report might be attributed to a complex interplay between different factors, such as genetic heterogeneity in weight loss response to GLP-1RA and other complex behavioral effects.
Over one and a half decades following GLP-1RA entering the market, liraglutide and semaglutide have demonstrated superiority in the normalization of glycaemia while markedly reducing the risk of major adverse cardiovascular and renal outcomes in patients with T2D; and have also shown significant weight reduction potential in patients with and without diabetes in large RCTs (as part of Phase 3 development programs), including SCALE, LEADER, SUSTAIN, STEP, SURPASS, and SURMOUNT programs [9,11,15,16]. Semaglutide at a daily dose of 0.4 mg sc revealed a capacity to reduce weight with a magnitude of 18.0% from baseline after a year of treatment among patients with obesity, while liraglutide, as an active control, demonstrated 9.2% mean weight loss. The proportion of patients achieving ≥ 5%, ≥10%, ≥15% and ≥20% weight loss was, 96%, 78%, 63% and 43% among those on semaglutide, and 72%, 41%, 20% and 6% with liraglutide, respectively [15].The pivotal STEP 1 Trial, investigating semaglutide 2.4 mg weekly compared to placebo, showed mean weight loss of 16.9% over one year in subjects with overweight and obesity, but not T2D [25]. Proving the dose-dependent effect of semaglutide, among the cohort of patients with T2D in STEP 2, weight loss achieved on semaglutide 2.4 mg once-weekly sc over 68 weeks of treatment was 10.6% vs. 7.5% on semaglutide 1.0 mg once-weekly sc and 3.1% on placebo (product-estimand) [28]. In STEP 3, adults with excess weight treated-as-intended with semaglutide 2.4 mg once weekly for 68 weeks as an adjunct to IBT achieved a significantly greater weight loss of 17.6% vs. 5.0% in the placebo group [29]. This was complemented by greater improvements in cardiometabolic risk factors, such as waist circumference and systolic blood pressure [28,29]. The observed ≥ 5%, ≥10%, ≥15% and ≥20% TWL attained by treatment completion were 90%, 80%, 60% and 39% among patients on semaglutide compared to 50%, 27%, 13% and 4% on placebo [28,29]. In STEP 4, adults with excess weight who continued on semaglutide 2.4 mg once-weekly sc for 48 weeks attained an additional 7.9% weight loss vs. 6.9% weight gain among those who were switched to placebo [30]. At 68 weeks, the mean weight loss in study subjects maintained on semaglutide 2.4 mg was 17.4% [30]. Along with weight reduction, semaglutide at a dose of 2.4 mg demonstrated its superiority over placebo in reducing mortality from cardiovascular causes in patients with preexisting cardiovascular disease and overweight or obesity without diabetes by about 20% [31].
Similarly, tirzepatide, offering a combination of GLP-1RA and a glucose-dependent insulinotropic polypeptide (GIP) agonist, demonstrated comparable results with 20.9% weight loss in patients with excess weight without T2D and 14.7% in patients with T2D after 72 weeks of treatment (treatment-regimen estimands) in SURMOUNT-1 and 2 RCTs [14,17]. SURMOUNT-3 showed that after a 12-week intensive lifestyle intervention, patients on tirzepatide experienced an additional 18.4% weight loss compared to patients on placebo who achieved 2.5% weight gain [32]. Finally, in SUMROUNT-4 patients with excess weight showed weight regain when tirzepatide was withdrawn, whereas patients continuing on tirzepatide continued to lose weight [33].
Because the mean weight loss of 8.0% seen in phase 3 trials for liraglutide 3.0 mg was significantly inferior, the utilization of semaglutide and tirzepatide has dwarfed the use of the latter. However, there are clinical scenarios where liraglutide may be favored.
First and foremost is cost. For example, the retail costs for semaglutide 2.4 mg and tirzepatide 15 mg exceed $1300 and $1000 in the US, respectively [34]. Many commercial payers exclude AOMs from policy benefits, and many jurisdictions do not cover AOMs under their insurance plans and prohibit payments for AOMs. Effective anti-obesity therapies are therefore out of reach for millions of people living with excess weight. In June 2024, liraglutide 1.8 mg became available generically. Although it is available at a high cost of approximately $400 to $700 per month, this represents an almost 50% reduction in price [35]. Additionally, for patients where there may exist more of a concern for serious gastrointestinal side effects, liraglutide may be more attractive due to its shorter half-life. If it needs to be discontinued, the adverse symptoms may resolve more quickly relative to those with longer half-lives, such as semaglutide or tirzepatide. Under any of these circumstances, it would seem worthwhile to try liraglutide since the search for good- or super-responders in the current era involves a “trial and error” approach.
Overall, weight loss outcomes observed in our series and the above-mentioned RCTs are approaching outcomes comparable to bariatric surgery but without the short- and long-term surgical risk [36]. While bariatric surgery remains the gold standard for weight loss, a surgical approach is not ideal for many patients due to medical, psychological or accessibility barriers. Many patients are not candidates for bariatric surgery, and in 2019, bariatric surgery was available to only 1 in 171 Canadians living with severe obesity [37]. This statistic is compounded by the fact that <1% of people who qualify for bariatric surgery will have the procedure, and more than half of eligible patients will decline surgery when offered [38,39]. Furthermore, a growing body of evidence supports the notion that weight loss following bariatric surgery occurs primarily through hormonal changes, with GLP-1 and peptide YY playing a dominant role, leading to improved eating control and a variety of positive metabolic effects [40,41,42].
From an economic perspective, bariatric surgery may lead to substantial cost savings in the long run compared to GLP-1RA due to their high cost [43]. However, this cost-effectiveness comparison is challenging as suboptimal response and recurrent weight gain are common after metabolic bariatric procedures, and pharmacologic treatment with GLP-1RA is warranted and effective for many patients in the post-surgical period [44]. There is an emerging, growing body of evidence supporting the utility of GLP-1RAs post-bariatric surgery to address suboptimal weight loss or weight gain after the procedures [45,46]. Many experts, therefore, conclude that bariatric surgery alone is not scalable to match the societal burden of disease and that pharmacologic strategies should be pursued in appropriate patients [47]. Ideally, pharmacological and surgical treatment options can be used in conjunction.
Obesity is a chronic progressive multifactorial disease requiring long-term management, which should involve assessing and addressing medical, psychological and social determinants, which is best done at the primary care level with a special emphasis on early intervention. The Canadian Adult Obesity Clinical Practice Guidelines recommend using pharmacotherapy in conjunction with medical nutrition therapy, physical activity and psychological interventions for weight loss and its maintenance in people living with obesity and adiposity-related complications [48].
Our study findings do support current guidelines that suggest a comprehensive lifestyle intervention be initiated in all patients, including offering pharmacotherapy to patients who qualify [48,49]. Nevertheless, many primary care providers are reluctant to initiate and monitor anti-obesity medications in their patients due to a lack of experience, time constraints, and inability to enroll patients in an ILI program.
Surprisingly enough, in SCALE and other large RCTs, weight loss among people with obesity on liraglutide 3.0 mg daily coupled with IBT at 1 year was 8.4% and 11.5%, while among those who received liraglutide in conjunction with standardized lifestyle counseling in SCALE 1, the weight loss was comparable and reached 9.2% [11,12,50]. In line with those findings, among people with obesity, O’Neil et al. and STEP 1 showed a weight reduction of up to 18.0% and 16.9% on semaglutide with standardized lifestyle intervention, while STEP 3 demonstrated similar weight loss attainment of 17.6%, but in this case in conjunction with IBT (product-estimands) [15,25]. Regular lifestyle counseling is an important component in the obesity management pathway and needs to be provided at initial and follow-up visits; however, counseling does not need to be extensive, time-consuming or replace evidence-based pharmaceutical intervention. The lack of substantial difference in GLP-1RA efficacy between monotherapy plus standardized lifestyle counseling versus monotherapy in conjunction with IBT is promising for the embedding of these agents into the routine primary care practice. A combination of a convenient regimen (self-administration), a dose-dependent pattern of weight loss allowing flexibility, and relative mildness and transience of adverse side effects is also encouraging.

Strengths and Limitations of the Study

The longitudinal prospective cohort design of our study, with the ability to reliably establish causality and temporality, was a strength. Due to the large number of patients being followed in our Bariatric Clinic, we were also able to select patients meeting study criteria and comprehensively assess the course of their treatment journey. Our study has several limitations, such as a relatively small sample size and inability to determine whether the characteristics shared by our patients can serve as predictors of good response.

5. Conclusions

A select number of patients with obesity will achieve results comparable to bariatric surgery using GLP-1RA monotherapy, such as liraglutide. The vast majority of such “super-responders” experienced benefits of liraglutide in the form of appetite suppression, reduction in frequency and intensity of cravings, and improvement in eating control and food choices. They were also compliant with recommendations on calorie and protein intake tracking, an increase in physical activity, and had their psychological issues and mental health conditions successfully managed. Pharmacological strategies are suitable for the vast majority of people living with excess weight and should be pursued in routine primary care and specialist practice. Given the numerous weight-related challenges faced by people with excess weight and the societal burden of obesity, GLP-1 analogues can assist in achieving long-term weight loss goals while being convenient and safe.

Author Contributions

Conceptualization, E.L. and R.M.; methodology, E.L., P.R., S.C. and R.M.; software, E.L. and O.T.; validation, E.L., E.G., D.S., A.J.M.-L. and R.M.; formal analysis, E.L. and O.T.; investigation, E.L. and R.M.; resources, E.L. and R.M.; data curation, E.L., P.R., S.C., O.T., A.M.S. and R.M.; writing—original draft preparation, E.L., E.G., P.R., S.C., O.T., D.S., A.J.M.-L., A.M.S. and R.M.; writing—review and editing, E.L., E.G., P.R., S.C., O.T., D.S., A.J.M.-L., A.M.S. and R.M.; visualization, E.L. and O.T.; supervision, E.L. and R.M.; project administration, E.L. and R.M. All authors have read and agreed to the published version of the manuscript.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Institutional Review Board Statement

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. The study was approved by the Institutional Review Board of the University of Alberta. (ID: Pro00076107; approval date: 7 December 2017).

Informed Consent Statement

Informed consent was obtained from all individual participants included in the study.

Data Availability Statement

Data are contained within the article.

Conflicts of Interest

Ellina Lytvyak: Advanz Pharma (grants/research support); Eduardo Grunvald: Novo Nordisk (consultant fees), Aardvark Therapeutics (research support), B2M Medical (advisory board), Elevai Labs (advisory board); Devika Shreekumar: None; Peter Rye: None; Sarah Cawsey: Novo Nordisk Canada (travel, speaker, and consultant fees), Bausch Health (consultant fees and travel); Olexandr Troshyn: None; Aldo J. Montano-Loza: Intercept Pharmaceuticals (served on the advisory boards); Arya M. Sharma: Novo Nordisk (travel, speaker, and consultant fees, advisory board), Merck (travel, speaker, and consultant fees), Bausch Health (advisory board); Renuca Modi: Novo Nordisk Canada (speaker and consulting fees), Takeda Pharma (development of educational materials, speaker fees), Bausch Health (speaker and consulting fees).

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Obesities 05 00063 g001
Figure 1. Weight change (kg) over the course of the study on liraglutide treatment. The blue dotted lines represent the median weight ± IQR.
Figure 1. Weight change (kg) over the course of the study on liraglutide treatment. The blue dotted lines represent the median weight ± IQR.
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Figure 2. Total Weight Loss (TWL, %) over time on liraglutide treatment. The blue dotted lines represent the median %TWL ± IQR.
Figure 2. Total Weight Loss (TWL, %) over time on liraglutide treatment. The blue dotted lines represent the median %TWL ± IQR.
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Obesities 05 00063 g003
Figure 3. Proportion of patients with various degrees of total weight loss over the course of the study.
Figure 3. Proportion of patients with various degrees of total weight loss over the course of the study.
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Table 1. Baseline patients’ characteristics.
Table 1. Baseline patients’ characteristics.
ParameterMedian (IQR) or % (n)
n = 21
Demographics
Female sex90.5% (19)
Age at liraglutide initiation, years50 (17)
Age ≥ 50 years old at liraglutide initiation52.4% (11)
Ethnicity, Caucasian90.5% (19)
Weight Status
Peak weight, kg127.6 (34.7)
Peak BMI, kg/m248.0 (17.1)
Class II or III obesity (BMI ≥ 35 kg/m2)100% (21)
BMI ≥ 50 kg/m242.9% (9)
EOSS stage
   00% (0)
   14.8% (1)
   290.5% (19)
   34.8% (1)
   40% (0)
Medical History
Obstructive sleep apnea57.1% (12)
Hypothyroidism42.9% (9)
Hypertension42.9% (9)
Osteoarthritis28.6% (6)
Type 2 diabetes23.8% (5)
Gastroesophageal reflux disease23.8% (5)
Dyslipidemia23.8% (5)
Polycystic ovary syndrome a15.8% (3)
Endometrial cancer a10.5% (2)
History of pulmonary embolism/deep vein thrombosis9.5% (2)
Steatotic liver disease9.5% (2)
Mental Health History and Psychological Evaluation
MDD42.9% (9)
GAD23.8% (5)
Binge eating disorder9.5% (2)
ADHD9.5% (2)
Personality disorder4.8% (1)
History of abuse, incl. sexual, physical, emotional28.6% (6)
History of addiction, incl. alcohol, recreational drugs9.5% (2)
Bariatric Surgery-related
History of bariatric surgery before liraglutide initiation14.3% (3)
Interested in bariatric surgery66.7% (14)
Proceeded with bariatric surgery post-liraglutide treatment, out of those interested78.6% (11)
Type of bariatric surgery performed
   Roux-en-Y gastric bypass54.5% (6)
   Laparoscopic sleeve gastrectomy45.5% (5)
ADHD, attention deficit hyperactivity disorder; BMI, Body mass index, kg/m2; EOSS, Edmonton Obesity Staging System; GAD, generalized anxiety disorder; MDD, major depressive disorder. a calculated for the female cohort only.
Table 2. Treatment-related characteristics.
Table 2. Treatment-related characteristics.
ParameterMedian (IQR) or % (n)
Pre-treatment (n = 21)
Weight, at liraglutide initiation (baseline), kg123.6 (34.9)
BMI, at liraglutide initiation, kg/m245.7 (7.4)
At their peak weight, at liraglutide initiation47.6% (10)
Lifestyle Modifications (n = 21)
Consistently tracking calorie intake95.2% (20)
Consistently tracking protein intake90.5% (19)
Established regulated meal pattern85.7% (18)
Calorie deficit achieved, kcal per day−651 (−323)
Met protein target85.7% (18)
Engaged in regular physical activity as tolerated80.9% (17)
Treatment Outcomes—Weight Status
16 weeks (n = 21)
   Weight, kg109.1 (23.3)
   Total Weight Loss, % from the baseline14.3% (3.7)
26 weeks (n = 20)
   Weight, kg99.3 (19.6)
   Total Weight Loss, % from the baseline18.7% (8.8)
52 weeks (n = 18)
   Weight, kg91.3 (18.4)
   Total Weight Loss, % from the baseline25.9% (9.6)
Last follow-up (n = 18)
   Weight, kg87.7 (16.1)
   Total Weight Loss, % from the baseline27.5% (7.4)
Benefits *
   Appetite reduction95.2% (20)
   Smaller portions95.2% (20)
   Healthier food choices90.5% (19)
   Increased satiety81.0% (17)
   Lower frequency and intensity of cravings66.7% (14)
   Improved control over eating19.0% (4)
   Decreased food pre-occupation14.3% (3)
Adverse events *
GI-related
   Constipation47.6% (10)
   Nausea42.9% (9)
   Dysgeusia33.3% (7)
   Belching14.3% (3)
   Dyspepsia14.3% (3)
Systemic
   Headache23.8% (5)
BMI, Body Mass Index, kg/m2 * only those with ≥10% incidence are presented.
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MDPI and ACS Style

Lytvyak, E.; Grunvald, E.; Shreekumar, D.; Rye, P.; Troshyn, O.; Cawsey, S.; Montano-Loza, A.J.; Sharma, A.M.; Modi, R. “Super-Responders” to Liraglutide Monotherapy and the Growing Evidence of Efficacy of GLP-1 Analogues in Obesity Management: A Longitudinal Prospective Cohort Study. Obesities 2025, 5, 63. https://doi.org/10.3390/obesities5030063

AMA Style

Lytvyak E, Grunvald E, Shreekumar D, Rye P, Troshyn O, Cawsey S, Montano-Loza AJ, Sharma AM, Modi R. “Super-Responders” to Liraglutide Monotherapy and the Growing Evidence of Efficacy of GLP-1 Analogues in Obesity Management: A Longitudinal Prospective Cohort Study. Obesities. 2025; 5(3):63. https://doi.org/10.3390/obesities5030063

Chicago/Turabian Style

Lytvyak, Ellina, Eduardo Grunvald, Devika Shreekumar, Peter Rye, Olexandr Troshyn, Sarah Cawsey, Aldo J. Montano-Loza, Arya M. Sharma, and Renuca Modi. 2025. "“Super-Responders” to Liraglutide Monotherapy and the Growing Evidence of Efficacy of GLP-1 Analogues in Obesity Management: A Longitudinal Prospective Cohort Study" Obesities 5, no. 3: 63. https://doi.org/10.3390/obesities5030063

APA Style

Lytvyak, E., Grunvald, E., Shreekumar, D., Rye, P., Troshyn, O., Cawsey, S., Montano-Loza, A. J., Sharma, A. M., & Modi, R. (2025). “Super-Responders” to Liraglutide Monotherapy and the Growing Evidence of Efficacy of GLP-1 Analogues in Obesity Management: A Longitudinal Prospective Cohort Study. Obesities, 5(3), 63. https://doi.org/10.3390/obesities5030063

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